Role of extraceullar vesicles in directing immunometabolic homeostasis after burn injury

细胞外囊泡在烧伤后指导免疫代谢稳态中的作用

• 批准号: 10337838
• 负责人: Bruce A Cairns
• 金额: $ 1.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337838
• 关键词: American; Animal Model; Anti-Inflammatory Agents; Antigen-Antibody Complex; Automobile Driving; Bacteremia; Bacterial Infections; Binding; Biological Response Modifiers; Burn Centers; Burn injury; Cells; Cessation of life; Clinical; Cytokine Signaling; Data; Development; Development Plans; Endothelial Cells; Ensure; Enzymes; Epithelial; Epithelial Cells; Experimental Designs; FRAP1 gene; Glycolysis; Goals; Graft Rejection; Grant; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immunomodulators; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Interleukin-10; Investigation; Lead; Leukocytes; Lung; Mediating; Metabolic; MicroRNAs; Molecular; Morbidity - disease rate; Mus; National Institute of General Medical Sciences; Opportunistic Infections; Outcome; PPAR gamma; Parents; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Phase; Phenotype; Plasma; Play; Pneumonia; Population; Pre-Clinical Model; Predisposition; Receptor Signaling; Research; Research Training; Role; Sampling; Sepsis; Signal Transduction; Stimulus; Testing; Tissues; Toll-like receptors; Training; Trauma; United States; Vesicle; arginase; burn model; career; career development; cytokine; experience; extracellular; extracellular vesicles; high risk; immune activation; immune function; improved; indexing; innate immune function; lung injury; macrophage; microvesicles; mortality; neutrophil; novel; parent grant; pre-doctoral; preclinical study; prognostic value; receptor expression; recruit; repository; response; severe burns; systemic inflammatory response

ABSTRACT The research and training plan put forth in this Diversity Supplement will build upon key findings generated under the parent application by the pre-doctoral candidate (Micah LaTrell Willis). This Research Plan and the Training Plan submitted will provide Mr. Willis with opportunities to not only build an intellectual and technical toolbox to propel him towards the next phase of his trainee/development but provide him the career development opportunities to ensure he obtains his short and long-term career goals. Thus, support from this this Diversity Supplement will empower Mr. Willis to own and drive his research, training, and career development plans. Severe burn injury is one of the most devastating forms of trauma, with mortality rates reaching up to 12% even in specialized burn centers. Combined inhalation injury further increases this mortality rate. The primary cause of mortality are opportunistic infections which occur days to weeks after the injury, often resulting in lethal pneumonias and/or sepsis from bacteremia. Burn-induced immune dysfunction underlies this prolonged susceptibility to infection. It is known that response to bacterial infections is induced and regulated by Toll-like Receptor (TLR) and associated MyD88 signaling, causing release of key inflammatory cytokines. With our parent NIGMS grant “Damage-Induced Activation of the TLR/mTOR/PPARg Axis Regulates the Immune Response After Burn and Inhalation Injury” (R01GM131124), we are currently investigating in human and pre-clinical studies that immune dysfunction after burn and inhalation injury involves aberrant MyD88-mediated TLR signaling by damage associated molecular pattern molecules (DAMPs) released after injury. This results in aberrant cytokine signaling, with macrophages, neutrophils and endothelial cells (EC) playing key roles. Extracellular vesicles have emerged as novel mediators of immune dysfunction across several immune pathologies. Microvesicles (MVs) are a class of extracellular vesicles that carry DAMPs, cytokines, and miRNAs, to regulate functions of recipient cells. We have found that MVs are a key reservoir for DAMPs, cytokines, and potent immune complexes after burn injury in humans and mice. Given our findings, and the key role of MVs in multiple immune conditions, we hypothesize that MVs drive the immune dysfunction associated with poor clinical outcomes in severe burn injury. These findings are highly synergistic with the Specific Aims of the parent grant. Using same patient and mouse tissue (utilizing our established pre-clinical model of burn and inhalation injury, and repository of human burn patient samples) derived during the parent grant’s experimental plan, we aim to further characterize the payload (Supplement Aim 1) and immune function (Supplement Aim 2) of MVs isolated from plasma after injury. This will allow us to incorporate MVs into the Immune Suppression Index (ISI) developed in the parent grant to identify burn patients at low and high risk for subsequent bacterial infection to improve prognostic value

抽象的 这种多样性补充剂中提出的研究和培训计划将基于根据 博士前候选人（Micah Latrell Willis）的父申请。该研究计划和培训 提交的计划将为威利斯先生提供机会，不仅建立一个智力和技术工具箱 推动他进入实习生/发展的下一阶段，但为他提供职业发展 确保他实现短期和长期职业目标的机会。这是从这种多样性中的支持 补充剂将使威利斯先生能够拥有并推动其研究，培训和职业发展计划。 严重的烧伤是最具破坏性的创伤形式之一，死亡率甚至达到12％ 在专门的烧伤中心。联合吸入损伤进一步提高了这一死亡率。主要原因 死亡率是机会感染，受伤后几天发生，通常导致致命 细菌血症的肺炎和/或败血症。燃烧引起的免疫功能障碍是延长的 感染的敏感性。众所周知，对细菌感染的反应是由Toll样诱导和调节的 受体（TLR）和相关的MYD88信号传导，导致关键炎症细胞因子的释放。和我们的父母在一起 NIGMS Grant“损伤引起的TLR/MTOR/PPARG轴的激活调节免疫反应 燃烧和吸入损伤之后”（R01GM131124），我们目前正在人类和临床前进行研究 燃烧和吸入损伤后免疫功能障碍的研究涉及异常MyD88介导的TLR 受伤后通过损伤相关的分子模式分子（湿）信号传导。这导致 异常的细胞因子信号传导，具有巨噬细胞，中性粒细胞和内皮细胞（EC）发挥关键作用。 细胞外蔬菜已成为几种免疫功能障碍的新型免疫功能障碍介质 病理。微泡（MV）是一类细胞外蔬菜，携带湿，细胞因子和miRNA， 调节受体细胞的功能。我们发现MV是潮湿，细胞因子和 人类和小鼠烧伤后有效的免疫复合物。鉴于我们的发现以及MV在 多种免疫条件，我们假设MVS驱动与临床不良相关的免疫功能障碍 严重烧伤的结果。这些发现与父母的具体目的高度协同 授予。使用同一患者和小鼠组织（利用我们已建立的临床前燃烧和吸入模型 在父母赠款的实验计划期间得出的伤害和人类烧伤患者样本的存储库，我们 旨在进一步表征有效载荷（补充AIM 1）和免疫功能（补充AIM 2）MVS 受伤后从血浆中分离出来。这将使我们能够将MV纳入免疫抑制指数（ISI） 在父母赠款中开发的，以识别以后细菌感染的低风险和高风险的烧伤患者 提高预后价值